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Uncovering genetic susceptibility to second malignant neoplasms in children and young adults: Findings from a tertiary oncology center in a resource-limited setting.

e22638 Background: Second malignant neoplasms (SMNs) represent a major cause of non-relapse mortality among long-term cancer survivors and currently account for 15–20% of new cancer diagnoses in national registries. While lifestyle exposures and prior cytotoxic therapies contribute to SMN risk, germline pathogenic variants in cancer-predisposition genes are increasingly recognized as a key driver. Data from low- and middle-income settings, however, remain limited. Methods: We reviewed the King Hussein Cancer Center registry to identify pediatric and young adult patients diagnosed with an SMN. Individuals who subsequently underwent germline testing in the adult or pediatric genetics clinics were included. Patients were classified as children (<15 years) or adolescents/young adults (AYAs; 15–39 years). Germline evaluation was performed using targeted multigene cancer-predisposition panels. Demographic features, timing and pattern of malignancies, and genetic findings were analyzed to identify potential hereditary syndromes contributing to SMN risk. Results: Of 244 patients with SMNs, 76 (28 children; 48 AYAs) underwent germline testing. Median age at first cancer diagnosis was 29 years (0.8–38.9), at second cancer 38 years (5–80), and at third cancer 35 years (16–72). Most patients had metachronous tumors (n=53, 70%), followed by synchronous (n=20, 26%) and complex patterns (n=3, 4%). Germline variants were identified in 40 patients. Pathogenic/likely pathogenic variants were detected in 27 (35.5%) in genes including ATM, BRCA1, DICER1, LZTR1, TP53, RAD51D, MSH6, MLH1, PMS2, SDHC, NF2, VHL, and MUTYH . An additional 14 patients carried variants of uncertain significance in genes such as ALK, APC, BRCA2, BRIP1, CASR, DIS3L2, FH, KIT, MSH3, PALB2, POLE, POT1, PLCG2, RECQL4, RET, RAD51D, SMARCE1, and WT1 . Common identified syndromes included constitutional mismatch repair deficiency (CMMRD), Lynch syndrome, DICER1 syndrome, BRCA-related syndromes, and neurofibromatosis type 2. At last follow-up, 62 patients were alive with a median overall survival of 111 months (7–678). Conclusions: These findings underscore the strong association between germline cancer-predisposition variants and SMNs. Systematic genetic evaluation of cancer survivors with multiple malignancies is essential to enable early detection, tailored surveillance, and personalized therapeutic strategies, ultimately improving long-term survivorship outcomes in resource-limited settings.

Nationwide trends in mortality with concurrent colorectal cancer and chronic ischemic heart disease: A CDC WONDER analysis (1999–2020).

e15721 Background: Co-mortality from colorectal cancer (CRC) and chronic ischemic heart disease (CIHD) is increasingly relevant in an aging population, yet contemporary U.S. trend patterns and disparities are incompletely described. Methods: Using CDC WONDER Death data (1999–2020), we identified deaths listing CRC (ICD-10 C18–C20) and CIHD (I25). We calculated age-adjusted mortality rates (AAMRs) per 100,000 using the 2000 U.S. standard population and evaluated temporal changes with Joinpoint regression (annual percent change [APC] and average annual percent change [AAPC]), with stratification by sex, age group, race/ethnicity, U.S. Census region, and urban-rural status. Results: We identified 99,083 deaths with CRC and CIHD listed. Overall, AAMRs declined significantly (AAPC −4.37%, 95% CI −4.83 to −3.92; P < 0.05). Men had higher mortality than women (AAMR 3.10 vs 1.41), and both sexes showed significant overall declines (women AAPC −5.19%, 95% CI −5.93 to −4.46; P < 0.05; men AAPC −4.05%, 95% CI −4.61 to −3.49; P < 0.05). Segmentally, women declined significantly from 1999–2006 (APC −4.72%, P < 0.05) and 2006–2017 (APC −7.27%, P < 0.05), followed by a non-significant incline thereafter. Men similarly declined significantly from 1999–2006 (APC −4.04%, P < 0.05) and 2006–2016 (APC −6.01%, P < 0.05), with a later non-significant reversal. By age, the 45–54 group showed a non-significant upward trend (APC 1.32%, 95% CI −0.05 to 2.70; P = 0.058), while ages 55–64 transitioned from a significant decline through 2017 (APC −3.77%) to a significant increase thereafter (APC 9.76%). Racial/ethnic burdens were highest among non-Hispanic (NH) White (AAMR 2.15) and NH Black individuals (AAMR 1.94), and AAMRs declined significantly across groups (e.g., Asians AAPC −4.34%, P = 0.013; NH Black AAPC −4.34%, P < 0.05; NH White AAPC −4.33%, P < 0.05; and Hispanics AAPC −4.27%, P < 0.05). Regionally, AAMR was highest in the Northeast (2.54) and Midwest (2.37); all regions declined significantly overall (e.g., Northeast AAPC −5.54%, P < 0.05; South AAPC −3.18%, P < 0.05), with a non-significant rebound in the Northeast after 2018. Nonmetropolitan areas had higher AAMR than metropolitan areas (2.47 vs 1.99), and both showed significant overall declines (metro AAPC −4.60%, P < 0.05; nonmetro AAPC −3.26%, P < 0.05). State AAMRs ranged from 0.94 (Utah) to 3.38 (West Virginia). Conclusions: CRC–CIHD co-mortality overall declined substantially from 1999–2020 but has recently plateaued, with concerning midlife increases and persistent rural and regional disparities. These findings support targeted, equity-focused integration of CRC screening/early detection with cardiovascular risk prevention and management, particularly for vulnerable subgroups.

Bulumtatug fuvedotin (BFv; 9MW2821) plus toripalimab in patients with locally advanced or metastatic urothelial carcinoma (la/mUC): Follow-up results from a phase 1b/2 study.

4518 Background: Nectin-4 is an adhesion molecule that is highly expressed in variety of solid tumors, especially in urothelial cancer, cervical cancer, esophageal cancer and breast cancer. BFv is a novel site-specific ADC targeting Nectin-4, and Toripalimab is a novel recombinant humanized anti-PD-1 monoclonal antibody. Previous results of BFv and Toripalimab in la/mUC patients have shown promising efficacy and well-tolerable toxicity. Here we report follow-up results of BFv and Toripalimab in la/mUC patients. Methods: This is an open-label, multicenter, phase 1b/2 study to evaluate the safety and efficacy of BFv combined with Toripalimab in la/mUC. Patients received BFv (1.0 or 1.25mg/kg) on D1/D8 and Toripalimab (240mg) on D1, 21 days per cycle. Primary objective was safety, and secondary objectives were efficacy, pharmacokinetics and immunogenicity. Results: As of 1 Dec 2025 (median follow-up time: 16.0 months), 47 assessable patients with la/mUC were enrolled and received the combination therapy of BFv and toripalimab. 7 of them (3 received BFv 1.0mg/kg; 4 received BFv 1.25mg/kg) have been previously treated for la/mUC and other 40 (all received BFv 1.25mg/kg) were treatment-naïve patients. In the overall population, ORR was 83.0% (95%CI 69.2-92.4), CR rate was 12.8%. All CR patients were still on treatment and the longest treatment duration has already exceeded two years. DCR was 89.4% (95%CI 76.9-96.5), median PFS was 12.9 months (95%CI 6.5-NA) and median DOR was not reach. Median OS also was not reach, OS rate at 18 months was 68.1% (95%CI 52.7-79.4). Subgroup analysis showed significant benefits to all patients, which might indicate that compared to traditional chemotherapy, BFv plus toripalimab could bring patients greater benefits and a longer survival time, especially in those elderly and patients with impaired kidney function. Safety profile was consistent with previous results, and there was no other new safety signals of BFv or toripalimab observed in this study. Conclusions: BFv plus toripalimab in patients with la/mUC demonstrated remarkable efficacy and well-tolerated safety profile. A pivotal phase 3 study is ongoing currently. Clinical trial identification: NCT06592326 , NCT06079112 .

Intracranial activity of sacituzumab govitecan in HER2-negative breast cancer brain metastases: A systematic review and meta-analysis.

e14009 Background: Patients with HER2-negative metastatic breast cancer who develop brain metastases face a critical therapeutic gap, as most systemic agents show limited central nervous system (CNS) penetration and intracranial efficacy. Sacituzumab govitecan (SG), a TROP-2–directed antibody–drug conjugate, has demonstrated survival benefit in advanced breast cancer, yet its intracranial activity remains poorly characterized. We conducted the first systematic review and meta-analysis focused specifically on the intracranial efficacy of SG in breast cancer brain metastases (BCBMs). Methods: We systematically searched PubMed, Embase, and Cochrane databases through November 2025 for clinical trials and observational studies reporting outcomes of SG in patients with documented BCBMs. Endpoints included overall survival (OS), progression-free survival (PFS), intracranial PFS (IC-PFS), overall response rate (ORR), disease control rate (DCR), intracranial ORR (IC-ORR), and intracranial DCR (IC-DCR). All analyses were restricted to cohorts with confirmed brain metastases. Random-effects models were applied, and heterogeneity was assessed using I² statistics. The protocol was registered in PROSPERO (CRD420251161992). Results: Eleven studies (2 prospective trials, 9 observational cohorts) comprising 313 patients with BCBMs were included. Median age ranged from 48 to 61.5 years, with median follow-up of 6.7–17.5 months. Among evaluable patients, 75% had stable brain metastases at treatment initiation. The pooled median OS was 8.4 months (95% CI 6.7–10.5; I²=0%), and median PFS was 3.8 months (95% CI 2.8–5.3; I²=67.8%). Importantly, SG demonstrated consistent intracranial activity, with a pooled median IC-PFS of 2.9 months (95% CI 1.7–4.9; I²=0%). While the pooled systemic ORR was modest at 10.7% (95% CI 0–37.9; I²=86.8%), the intracranial ORR reached 31.7% (95% CI 15.5–54.0; I²=58.2%). Disease control was more consistent across studies, with a pooled DCR of 45.4% (95% CI 33.9–57.5; I²=0%) and an IC-DCR of 55.6% (95% CI 42.2–68.1; I²=0%). Conclusions: SG demonstrates reproducible intracranial disease control and a clinically meaningful intracranial response rate in patients with HER2-negative BCBMs, an area of profound unmet need. Despite modest systemic response rates, the disproportionate intracranial activity observed supports SG as one of the few systemic therapies with potential CNS efficacy in this population. These findings provide a strong rationale for prospective trials incorporating brain-specific endpoints.

Efficacy and safety of surufatinib combined with immune checkpoint inhibitors plus chemotherapy in patients with biliary tract cancers: A real-world study.

e16222 Background: The management of advanced biliary tract cancers (BTC) remains a significant clinical challenge. Although the combination of immune checkpoint inhibitors (ICIs) with gemcitabine and cisplatin has established a new first-line standard of care, the clinical benefits are still limited. Surufatinib, a novel oral TKI, shows preclinical anti-tumor immune potential, but robust clinical and real-world evidence for its combination with ICIs/chemotherapy in BTC is lacking. regarding the efficacy and safety of surufatinib in combination with ICIs and chemotherapy for BTC is currently lacking. Methods: This single-center retrospective real-world study (ChiCTR 2500100586) enrolled patients (pts) with BTC who received surufatinib combined with ICIs and chemotherapy. Patients were required to have at least one measurable lesion per RECIST 1.1 criteria. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS), Secondary endpoints included disease control rate (DCR), and overall survival (OS). Results: As of the latest data cut-off on June 1, 2026, a subset of the planned sample size had been enrolled. （N=12）The combination regimen showed promising anti-tumor activity, with a confirmed ORR of 41% (5/12), consisting of 0 complete responses (CR) and 5 partial responses (PR).The DCR was 66% (8/12)，The preliminary median PFS was estimated to be 7.3 months .The safety profile of the regimen was generally consistent with the known profiles of the individual agents, with no new or unexpected safety signals identified. The most common grade ≥3 treatment-related adverse events (TRAEs) included hepatic impairment (8%); neutropenia, thrombocytopenia, hypertension, and proteinuria (all 0%). Most adverse events were manageable with dose modifications and supportive care. Conclusions: In this real-world study of first-line treatment for advanced BTC, surufatinib combined with ICIs plus gemcitabine-platinum chemotherapy demonstrated encouraging preliminary efficacy and manageable safety. Through synergistic effects (anti-angiogenesis + immunomodulation + cytotoxicity), this triple therapy is expected to break through the current efficacy bottleneck of conventional chemotherapy for advanced BTC. Larger sample size and longer follow-up are needed to validate these findings. Clinical trial information: ChiCTR2500100586. Best tumor response and treatment- related advers evevts. Best Tumor Response evaluated Treatment-related adverse events Study Endpoint N=12 Adverse events N=12 ORR，N(%)【95% CI】 5（41%）(15.24~72.38) AEs，N(%) 11（91%） 95% CI (61.51~99.79) DCR，N(%)【95% CI 】 8（66%) (34.99~89.43) TEAEs N(%) 11（91%）95% CI (61.51~99.79) CR，N(%)【95% CI】 0（0%）(0.00~26.55) SAEs，N(%) 0（0%）95% CI ( 0.00~26.55) Surgery，N(%)【95% CI 】 1（8%）(0.21~38.43) irAEs，N(%) 1（8%）95% CI (34.99~89.43) mPFS 7.3（months） Grade≥3，N(%) 1（8%）95% CI (34.99~89.43)

Cancer outcomes, screening rates, and health behaviors by county-level poverty status.

e23128 Background: Persistent poverty is associated with enduring structural barriers to cancer prevention and care, a challenge further magnified in predominantly rural states in which access constraints place communities at risk for lower screening uptake and more advanced cancer diagnosis. However, little is known about differences in cancer-related health behaviors, screening rates, and outcomes by county-level poverty status. Thus, we sought to compare health behaviors, screening rates, and cancer outcomes by county-level poverty status in a rural state (Oklahoma). Methods: We classified Oklahoma counties as persistent poverty counties (PPCs), defined as having ≥20% of residents living in poverty for ≥30 years, based on the U.S. Economic Development Administration criteria (2022; 18 counties). We categorized current poverty counties (CPCs) as those with ≥20% of residents living in poverty in 2022 but not meeting PPC criteria, based on the Small Area Income and Poverty Estimates (2022; 24 counties). We categorized remaining counties as non-poverty counties (NPCs), with <20% of residents living in poverty (35 counties). We obtained county-level sociodemographic characteristics and health behaviors from the University of Wisconsin Population Health Institute County Health Rankings (2022). We gathered breast and colorectal cancer screening rates (2022) from the Centers for Disease Control and Prevention PLACES data repository. We obtained age-adjusted incidence and mortality rates from OK2Share for lung, breast, and colorectal cancers (2018–2022). We evaluated group differences across PPCs, CPCs, and NPCs using one way analysis of variance. Results: Among Oklahoma counties, average county rurality (85.9% [PPCs] vs 76.0% [CPCs] vs 62.2% [NPCs]; p=.011) differed significantly by county poverty status. Health behaviors also differed across county groups, with higher rates of smoking in PPCs (22.6% vs 19.9% [CPCs] vs 18.0% [NPCs]; p<.001) and physical inactivity (35.1% vs 32.8% [CPCs] vs 30.4% [NPCs]; p<.001). Cancer screening rates were lower in PPCs for colorectal cancer (50.9% vs 52.8% [CPCs] vs 54.3% [NPCs]; p<.001) and breast cancer (64.5% vs 66.9% [CPCs] vs 68.1% [NPCs]; p<.001). Notably, lung cancer incidence and age-adjusted mortality rates were highest in PPCs (incidence: 77.5 vs 70.0 [CPCs] vs 60.9 [NPCs] per 100,000; p=.001; mortality: 54.6 vs 50.7 [CPCs] vs 44.5 [NPCs] per 100,000; p=.003), while breast and colorectal cancer incidence and mortality did not differ significantly across county groups. Conclusions: At the county level in a largely rural state, PPCs had higher rates of smoking and physical inactivity, lower rates of cancer screening, and higher lung cancer incidence and mortality than CPCs and NPCs. Findings highlight the need for targeted strategies to enhance cancer prevention and optimize oncologic care delivery for individuals living in areas with persistent poverty.

First-in-world oral solution formulation of enzalutamide: Bioequivalence versus soft-gel capsule to support patient-centric drug delivery.

e17072 Background: Enzalutamide is a standard therapy for advanced prostate cancer. An oral solution formulation has been developed to improve patient convenience and to address the needs of patients with swallowing difficulties or those requiring alternative oral administration. This study evaluated the bioequivalence of a novel enzalutamide oral solution formulation compared with the reference soft-gel capsule formulation. Methods: This open label, randomized, two-treatment, two-period crossover study was conducted in healthy adult male subjects under fasting conditions. Subjects received a single 160 mg dose of the Test oral solution or the Reference soft-gel capsule in each period. Serial blood samples were collected up to 72 hours post dose. Primary pharmacokinetic endpoints included maximum plasma concentration and area under the plasma concentration time curve from time zero to 72 hours. Parameters were analyzed using analysis of variance on log-transformed data. Bioequivalence was concluded if the 90 percent confidence intervals for the Test to Reference geometric mean ratios were within the predefined acceptance range of 80 to 125 percent. Results: 37 subjects completed both periods and were included in the pharmacokinetic analysis. For the Reference, geometric mean maximum plasma concentration was 6276.85 ng/mL and AUC from time zero to 72 hours was 126902.97 ng·h/mL. For the Test oral solution, geometric mean maximum plasma concentration was 6594.35 ng/mL and AUC from time zero to 72 hours was 128485.08 ng·h/mL. The Test to Reference geometric mean ratios were 105.06 percent for maximum plasma concentration with a 90 percent CI of 98.97 to 111.52 percent and 101.25 percent for AUC from time zero to 72 hours with a 90 percent confidence interval of 98.35 to 104.23 percent. Both parameters met bioequivalence criteria. No clinically relevant safety findings were reported. Conclusions: The enzalutamide 160 mg per 5 mL oral solution was bioequivalent to the reference soft-gel capsule formulation under fasting conditions, with comparable systemic exposure and favorable tolerability. This first-in-world oral solution formulation represents a patient-centric alternative that may support improved accessibility for elderly patients with swallowing difficulties, increases compliance and warrants further clinical and therapeutic application. Statistical results of log transformed test versus reference product enzalutamide. Parameter Test Reference Difference n %CV Geometric Mean (Test) Geometric Mean (Reference) Ratio (%) 90% CI Power Conclusion LN_Cmax 8.7940 8.7446 0.0353 35 15.22% 6,594.3473 6,276.8537 105.06% 98.97% to 111.52% 99.98% YES LN_AUC0-72 11.7636 11.7512 0.0172 35 7.37% 128,485.08 126,902.97 101.25% 98.35% to 104.23% 100 % YES

Unmasking the clinical impact of SGLT-2 inhibitors in stage IV colorectal cancer: A real-world multicenter analysis.

e15628 Background: Colorectal cancer (CRC) is the fourth most diagnosed cancer in the United States, and stage IV CRC has a 5-year survival rate of 11%–14%. One risk factor for the development of CRC is Diabetes Mellitus (DM). Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are associated with improved survival in patients with CRC and DM, but their impact in stage IV CRC remains unclear. This study explores the effects of SGLT2i on mortality, ICU admissions, and other clinical outcomes in diabetic patients diagnosed with stage IV CRC. Methods: We performed retrospective analysis using deidentified, aggregate patient data from the TriNetX research network. Patients aged 18-75 with stage IV CRC and DM were sorted into two cohorts: those prescribed SGLT2i after being diagnosed with DM and stage IV CRC vs. those with no SGLT2i use. Patients were then 1:1 propensity matched on variables such as demographics, comorbidities, procedures, exposure to other diabetic medications, and systemic therapies for CRC. Following matching, there were 1614 patients in each cohort. Multivariable logistic regression analysis was performed to define adjusted Odds ratios (OR) with 95% confidence intervals. Results: SGLT2i exposure demonstrated improved clinical outcomes. There was a reduction in all-cause mortality (OR 0.359, 95% CI 0.306–0.421) and ICU admissions (OR 0.750, 95% CI 0.593–0.947). These patients also exhibited reduced rates of thromboembolic events (OR 0.575, 95% CI 0.438-0.755), bowel obstruction (OR 0.510, 95% CI 0.375-0.695), and gastrointestinal bleeding (GIB) (OR 0.600, 95% CI 0.452-0.796), as well as a decreased need for blood transfusions (OR 0.410, 95% CI 0.293-0.573). However, there was no significant effect on major adverse cardiac events (OR 1.125, 0.798-1.587) or rates of biliary obstruction/cholangitis (OR 0.850, 95% CI 0.523-1.381). Conclusions: DM and Stage IV CRC patients who were prescribed SGLT2i were found to have lower rates of all-cause mortality, ICU admissions, thromboembolic events, bowel obstruction, GIB, and blood transfusion requirements. These findings suggest SGLT2i may provide benefits that aid in reducing systemic and treatment-limiting complications in this high-risk population. Further investigation is required to determine if SGLT2i may serve a role in adjunctive therapy to maximize patient outcomes and enhance the overall care of stage IV CRC patients. Effects of SGLT2i in patients with Stage IV CRC and DM. Outcome Odds ratio (95% CI) P value All-cause mortality 0.359 (0.306–0.421) <0.001 Blood transfusion 0.410 (0.293–0.573) <0.001 ICU admission 0.750 (0.593–0.947) 0.015 Thromboembolic events 0.575 (0.438–0.755) <0.001 Major adverse cardiac events (MACE) 1.125 (0.798–1.587) 0.501 Bowel obstruction 0.510 (0.375–0.695) <0.001 GI bleed 0.600 (0.452–0.796) <0.001 Biliary obstruction/cholangitis 0.850 (0.523–1.381) 0.511

Transfusion effectiveness and clinical outcomes in acute leukemia: Do poor responders have worse outcomes?

e18614 Background: Transfusion support is essential for patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), yet most literature focuses on hemoglobin or platelet thresholds rather than transfusion effectiveness. In practice, clinicians often assume predictable post-transfusion increments even in the setting of active leukemia, inflammation or marrow failure. We evaluated transfusion response and STAT priority timing in AML and ALL to determine whether these factors were associated with length of stay (LOS) and in-hospital mortality. Methods: We conducted a retrospective cohort study of hospitalized adults (≥18 years) with AML or ALL who received RBC or platelet transfusions at a tertiary academic center from October 2022 to October 2025. Analyses were restricted to transfusion episodes with available pre- and post-transfusion lab values. Primary outcomes were transfusion response for RBCs (ΔHgb, g/dL) and platelets (Δplatelet, ×10⁹/L). Adequate response was defined as ΔHgb ≥1.0 g/dL or Δplatelet ≥10×10⁹/L. Secondary outcomes included LOS and in-hospital mortality. We used regression models to evaluate associations with STAT priority orders. Results: Among 115 patients, 544 RBC and 779 platelet transfusion episodes were evaluable. Median RBC increment was 0.8 g/dL; 39.7% achieved ≥1.0 g/dL and 18.4% showed no rise or a decrease. STAT orders were independently associated with smaller RBC (β −0.25 g/dL, p=0.016) and platelet increments (β −4.93×10⁹/L, p=0.005). Adequate RBC response was associated with shorter LOS (β −6.64 days, p<0.001), while adequate platelet response was strongly associated with lower in-hospital mortality (OR 0.62, p≈0.001). STAT priority orders were associated with shorter LOS for both RBC (β −11.82 days, p<0.001) and platelet episodes (β −13.29 days, p<0.001), with opposite mortality associations by product type, reflecting clinical acuity. Conclusions: Transfusion response in AML and ALL is variable, with fewer than half of RBC or platelet transfusions achieving expected lab increments. Adequate RBC response shortens LOS, while adequate platelet response reduces in-hospital mortality. STAT orders identify encounters with smaller increments but substantially shorter LOS, highlighting the role of clinical urgency. These findings support evaluating transfusions by “units effective” rather than “units administered.” This retrospective design limits adjustment for unmeasured clinical severity, underscoring the need for further multicenter studies. RBC Metrics Platelet Metrics Median ΔHgb (g/dL) 0.8 Median Δplatelet (×10⁹/L) 12 % Adequate response (≥1g/dL) 27.5% % Adequate response (≥10×10⁹/L) 43% % No rise or decrease 12.9% % No rise or decrease 15.6% STAT effect on ΔHgb (β,p) -0.25 (p=0.016) STAT effect on Δplatelet (β,p) -4.93 (p=0.005) Adequate response on LOS -6.64 (p<0.001) Adequate response on mortality 0.62 (p=0.001)

An interpretable machine learning model using routine clinicopathological variables to predict postoperative recurrence in early-stage NSCLC: Development and external validation.

e20053 Background: Recurrence risk after curative-intent surgery in early-stage (I–II) NSCLC remains heterogeneous. We developed and externally validated a machine-learning model to improve recurrence risk stratification for personalized postoperative management. Methods: We retrospectively evaluated a cohort of 724 patients with stage I–II NSCLC who underwent curative-intent resection. Recurrence was defined as radiologic and/or pathologic evidence of relapse, and a total of 52 patients experienced disease recurrence. A Random Forest (RF) classifier was trained using 11 routinely collected variables and benchmarked against Logistic Regression (LR) within a nested cross-validation pipeline to prevent data leakage. MICE imputation was performed strictly within the cross-validation folds. The independent external cohort (n = 50) was intentionally enriched (25 recurrence/25 no recurrence) to enable stable discrimination testing. Clinical utility was assessed via Decision Curve Analysis (DCA), and interpretability was established using SHapley Additive exPlanations (SHAP). Results: Median follow-up was 4.2 years. The Random Forest model outperformed Logistic Regression in both internal (ROC-AUC 0.704 vs 0.64) and external validation (ROC-AUC 0.71 vs 0.57). In internal out-of-fold analysis, the RF model achieved a sensitivity of 73.1% and specificity of 63.5% at a Youden-optimal threshold of 0.41. External validation demonstrated a consistent ROC-AUC of 0.71 (95% CI: 0.56–0.85). SHAP analysis identified tumor size, FEV1/FVC ratio, STAS, T-stage, and necrosis as the most influential predictors of recurrence. DCA showed superior net clinical benefit compared to "treat-all" or "treat-none" strategies. Conclusions: Our interpretable Random Forest model demonstrates stable discrimination and external validation using standard clinical data. This approach may support risk-adapted surveillance and guide postoperative decision-making, warranting prospective multicenter validation.

Breast cancer expanded multigene panel testing in hereditary cancer patients, from the Baja California, Mexico–USA border region.

e12513 Background: Hereditary cancer syndromes account for approximately 5–10% of all cancer cases. Germline pathogenic variants in BRCA1 and BRCA2 remain the most recognized causes of hereditary breast and ovarian cancer (HBOC); however, exclusive BRCA-centered testing may underestimate the genetic heterogeneity of cancer susceptibility, particularly in underrepresented populations. In Mexico, access to comprehensive genetic testing remains highly centralized, limiting diagnostic yield and equitable care. Methods: We conducted a retrospective analysis of 193 individuals with breast cancer, referred for hereditary cancer evaluation, from January 2023 to Decemeber 2025 in a single center Hospital General de Tijuana at Tijuana, Mexico (a city in the Mexico–US border region). All patients met NCCN criteria for genetic testing and were assed by the medical genetics department. Genetic testing included BRCA1/2 -only analysis in a limited number of cases and predominantly next-generation sequencing multigene panels (70 genes). Diagnostic yield and gene distribution were analyzed. Results: Among the 193 individuals tested, 33 (17.0%) carried pathogenic or likely pathogenic variants, 74 (38.3%) harbored at least one VUS, and 86 (44.6%) had negative results. Pathogenic variants in BRCA1 (n = 12, 36.4%) and BRCA2 (n = 13, 39.4%) accounted for 75.8% (25/33) of all positive findings. Importantly, 24.2% of pathogenic variants were identified in non-BRCA genes, including TP53, CHEK2, PALB2, BLM, BRIP1, and FLCN, highlighting clinically actionable diagnoses beyond BRCA1/2. Analysis of VUS demonstrated substantial genetic heterogeneity, with variants distributed across genes involved in DNA damage response and repair, mismatch repair, polymerase proofreading, and hereditary tumor syndromes. T he most frequently affected genes were APC (n = 7, 9.5%) and ALK (n = 5, 6.8%), followed by AXIN2 (n = 4, 5.4%). Variants in DNA damage response and repair pathways were common, including ATM, CHEK2, BRCA2, POLE, POLD1, NBN, and BLM. Additionally, alterations were observed in mismatch repair genes associated with Lynch syndrome. Conclusions: Our findings confirm that while BRCA1/2 remain the predominant contributors to hereditary cancer susceptibility, a significant proportion of clinically relevant diagnoses in this population would be missed without expanded multigene panel testing. The high burden of VUS highlights the critical need for variant reclassification strategies, functional validation, and population-specific genomic data. Decentralizing access to comprehensive genetic testing and strengthening local expertise in variant interpretation are essential to improving hereditary cancer care in Mexico and similar resource-limited settings.

Perceived financial barriers and delayed hospital care for breast and cervical cancer in Nigeria: A qualitative study.

e13522 Background: Breast and cervical cancers are leading causes of cancer-related morbidity and mortality in Nigeria, with disproportionately poor outcomes in rural communities due to delayed diagnosis and advanced-stage presentation. While financial barriers to hospital-based cancer care are frequently cited, the role of community perceptions and misinformation about hospital costs is less well understood. This qualitative study explored community perspectives on hospital utilization for breast and cervical cancer care in Nigeria. Methods: Qualitative in-depth semi structured interviews were conducted with consenting community leaders, religious leaders, women influencers, policy makers and traditional healers, five in each group and 4 focus group discussions with community women from July to September 2024 in 2 communities in Federal Capital Territory (FCT) Nigeria to explore healthcare-seeking behaviours, perceptions of hospital affordability, and barriers to accessing hospital-based services for breast and cervical cancer screening, diagnosis, and treatment. Data were analysed thematically using an inductive approach and coded using Dedoose software. Results: Participants reported that fear of high hospital costs discourages early hospital visits for breast lumps, abnormal vaginal bleeding, and other symptoms suggestive of breast or cervical cancer. Many residents assume hospitals are unaffordable and therefore delay care or first seek treatment from pharmacies or informal providers. Participants described hospital practices in which patients receive treatment and medications without immediate payment, with fees requested only for accommodation or after recovery; however, awareness of these practices was limited. Transportation challenges, long distances to hospitals, intimidating hospital environments, and fear of hidden charges further compounded delays. Participants emphasized that bringing services closer to rural communities and improving awareness of affordable care options would increase hospital utilization. Conclusions: In Nigeria, perceived financial barriers, compounded by transportation challenges and misinformation, significantly delay hospital-based care for breast and cervical cancer, contributing to late-stage presentation. Community-centred awareness strategies, clearer communication about payment policies, and decentralization of screening and diagnostic services are critical to improving early detection and cancer outcomes, especially in rural settings.

Financial vulnerability among U.S. cancer survivors: Differences by veteran status and VA health care utilization in the National Health Interview Survey, 2020–2024.

1561 Background: Current national comparisons of financial factors affecting cancer care among Veterans and non-Veteran adults with a self-reported history of cancer are limited. Moreover, little is known about how financial vulnerability influences Veterans receiving care primarily through the VA system versus in community settings. We hypothesize that Veteran status and primary care setting (VA vs. community) are associated with differences in financial vulnerability and related barriers to medical care among U.S. adult survivors of cancer. Methods: We pooled 2020–2024 National Health Interview Survey data (n=19,410) to examine associations between Veteran status, VA care use, and financial vulnerability among adult survivors from cancer (including non-melanoma skin cancer). Missing data were addressed using multiple imputation leading to an analytic sample size n=18,846. Survey-weighted logistic regression models accounted for complex sampling and adjusted for age, sex, cancer site, number of cancers, years since diagnosis, poverty ratio, and survey year. Analyses were limited to years when outcomes were collected. Two comparisons were conducted to understand the unique social factors Veterans face compared to non-Veteran patients and differences between primary setting of Veteran care: Model(A) Veterans vs. non-Veterans and (B) VA primary users vs. non-primary VA users. Binary outcomes included delayed care due to cost, delayed care due to transportation barriers, inability to afford care, unpaid medical bills, insurance gaps, medication cost-skipping, and inability to pay expenses. Sensitivity analyses compared weighted and unweighted models. Results: The analytic sample of adult survivors from cancer was n=18,846 from 2020–2024 (mean age 68 years; 43% male) and included 2,511 (13%) who self-reported as Veterans (mean age 74 years; 94% male). Adjusted models showed Veteran status was associated with higher odds in care delay due to transportation barriers (OR 1.57; 95% CI, 1.13-2.19) and lower odds of worry regarding unpaid medical bills (OR 0.79; 95% CI, 0.68-0.91) and difficulty obtaining medical care due to cost OR 0.78(0.63-0.98). All other compared variables were not significant. Among Veterans, those who primarily used the VA had lower odds of delaying care due to cost (OR 0.34; 95% CI, 0.17-0.69), not obtaining medical care due to cost (OR 0.50; 95% CI, 0.35-0.72), and skipping medication due to cost (OR 0.25; 95% CI (0.12-0.49). Sensitivity analyses supported these patterns. Conclusions: Veterans who are primarily VA users have cost-related vulnerability without a difference in delaying care to non-Veteran counterparts. Such systems that remove financial hardship may be an approach to improve care for survivors from cancer in the U.S.

Outcomes of infectious workup and antibiotic use during tarlatamab initiation in patients with advanced neuroendocrine carcinomas.

e23307 Background: Tarlatamab has improved outcomes in extensive-stage small cell lung cancer (ES-SCLC) and is under investigation in other neuroendocrine carcinomas (NEC). Patients are monitored for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) during tarlatamab. As it can be difficult to discern CRS/CANS from sepsis, we evaluated culture acquisition patterns and empiric antibiotic use during tarlatamab initiation. Methods: We conducted a retrospective chart review of patients with advanced NEC treated with tarlatamab at Yale Cancer Center (2023–2025) through an IRB-approved protocol. Data cutoff was December 20, 2025. Antibiotics appropriateness was determined by culture positivity and clinical review. Results: Thirty-four patients were identified. Smoking history varied (20 former, 10 current, 4 never). Histologies included SCLC (n = 24), large cell neuroendocrine carcinoma (LCNEC; n = 2), mixed SCLC/LCNEC (n = 1), mixed LCNEC/adenocarcinoma (n = 1), prostate NEC (n = 2), nasal cavity NEC (n = 1), and small bladder cell carcinoma (n = 1). 30/34 patients received ≥1 dose of tarlatamab. At C1D1, 33 patients were observed inpatient and 1 outpatient. Thirty continued to C1D8 (29 inpatient, 1 outpatient), and 27 to C1D15 (24 outpatient, 3 inpatient). At C1D1 and C1D8, CRS and/or ICANS were noted in 19/34 and 9/30 patients respectively (Table 1). Cultures were obtained for 20/64 encounters: 18 blood, 12 urine, 1 cerebrospinal fluid, 2 sputum, and 1 pleural fluid. Documented reasons for culture were fever (n = 17), hypotension (n = 4), hypoxia (n = 3), altered mental status (n = 5), and dysuria on admission (n = 1). Most cultures (88.2%) were negative after 5 days of incubation. Four urine cultures were positive: Klebsiella pneumoniae (n = 2), Staphylococcus aureus (n = 1), and Serratia and Lactobacillus species (n = 1). Nine patients received antibiotics, with 88% intravenous. No cultures or antibiotics were documented during C1D15. Retrospective adjudication of clinical details and culture data deemed antibiotics unnecessary in all cases, as symptoms improved with CRS/ICANS-directed therapy, or an organism was deemed a colonizer. Conclusions: During tarlatamab initiation, documented culture growth was rare and antibiotics were deemed unwarranted after clinical review. Routine infectious workup and empiric antibiotic initiation during tarlatamab observation may be unnecessary and should be reserved for clear evidence of infection or clinical deterioration requiring escalation of care despite treatment for CRS/ICANS. These results support protocol changes to reduce unnecessary testing, antibiotic exposure, and patient discomfort. Patient characteristics. C1D1 (N=34) C1D8 (N=30) Fever (≥38°C) 14 5 CRS G1-2 14 7 CRS G3-4 3 1 ICANS G1-2 6 4 ICANS G3 2 0 Patients cultured 13 7 Positive cultures (urine) 1 3 Antibiotics given 6 3

“Probably a Little Bit of a Hill to Climb”: A qualitative study of emergency department providers’ perceptions of nonpharmacological pain treatment

Background Nonpharmacological strategies are advocated as evidence-based treatment options for pain, yet these are rarely offered within the emergency department (ED) setting. Understanding how ED providers perceive these strategies can guide implementation efforts. Objective The objective of this study was to qualitatively examine ED provider perceptions of conventional and complementary nonpharmacological pain strategies. Methods Nine ED physicians from a single academic medical center completed a semi-structured interview conducted by a trained qualitative researcher. The interview focused on the provider’s current pain management approach and perceived benefits, barriers, and facilitators of nonpharmacological pain treatments. Each interview was audio-recorded, transcribed verbatim, and analyzed using an iterative deductive–inductive approach. Findings were organized into themes and subthemes to inform a conceptual model of nonpharmacological intervention implementation. Results Six major themes emerged: 1) institutional context around intervention implementation, 2) professional beliefs about nonpharmacological pain interventions, 3) patient characteristics as a modifying factor, 4) intervention characteristics as a modifying factor, 5) process of implementation, and 6) engagement. Providers acknowledged benefits of nonpharmacological strategies, particularly for patients with chronic pain or history of opioid use. However, perceived barriers included negative patient perceptions of mind-body therapies, minimal ED provider training or education, limited time or care coordination support, and lack of physical space. Possible facilitators for integration included provider education, leadership support, and intervention tailoring. Conclusion ED providers recognize the potential value of nonpharmacological pain treatment strategies. However, both broad healthcare and ED-specific barriers to implementation may limit routine use in the ED. Future efforts for improving pain management in the ED should identify strategies to address implementation barriers of evidence-based nonpharmacological interventions.

Critical perspective review on green synthesis of zinc oxide nanoparticles: Explored wurtzite phase, characterization and real world applications

Programming novel intrinsically disordered proteins by directed evolution

Spatial differentiation and driving mechanisms of traditional villages based on geo-explainable artificial intelligence

MoChia1 is a GH18 reducing-end GlcNAc–releasing chitin oligosaccharide hydrolase from the rice blast fungus Magnaporthe oryzae

Correlation of immune remodeling linked to obesity with immunotherapy outcomes in cholangiocarcinoma: An externally validated international cohort study.

4134 Background: Obesity is an established risk factor for cancer, yet paradoxically may be associated with improved responses to immune checkpoint inhibitors (ICIs). We investigated whether obesity defines a clinically and biologically distinct cholangiocarcinoma (CCA) subtype when treated with ICIs. Methods: Retrospective analysis of Body Mass Index (BMI)-stratified patients (pts) with CCA treated at a single US center (US cohort) and enrolled in a prospective multicenter Italian registry (Italian cohort). High BMI was defined per CDC criteria (overweight 25.0-29.9; obesity ≥30 kg/m²), with cohort-specific cutoffs for analysis (US ≥30; Italy ≥25). Tumor microenvironment (TME) was profiled with bulk RNA-seq and CODEX multiplex imaging and body composition radiomics with TotalSegmentator tool in the US cohort. Chi-square, Pearson correlation or Wilcoxon tests were used to test associations with BMI; overall survival (OS) was assessed with Kaplan-Meier and Cox models. Results: 989 pts were included (661 US; 328 Italy). In the US and Italian cohorts, median age was 62 and 65 years, 51% and 47% were female, and 28% and 43% were obese and overweight, respectively. Metabolic comorbidities included diabetes (US: 15%; Italy: 19%), hypertension (US: 48%; Italy: 45%), and hyperlipidemia (US: 32%; Italy: 15%). Higher subcutaneous-to-visceral fat ratio was associated with improved OS with chemotherapy-ICI (HR 0.89; 95% CI 0.79-0.99; p = 0.036). In both cohorts, patients with high BMI treated with chemotherapy-ICI had significantly longer OS compared with lower-BMI patients (US: 31.6 vs 19.2 months, p = 0.005; Italy: 21 vs 12 months, p = 0.025). In multivariable models (US cohort) both obesity (HR 0.35; 95% CI 0.23-0.52, p < 0.0001) and higher visceral-to-subcutaneous fat ratio (HR 1.79; 95% CI 1.04-3.07, p = 0.037) were independently associated with OS. Combined genomic profiling (n = 906) showed a lower prevalence of KRAS alterations in high-BMI pts (OR 0.56, p = 0.006). RNA-seq (n = 86; obese = 37, non-obese = 49) demonstrated enrichment of fibroblast-associated signatures ( αSMA, PDPN, collagen IV, vimentin ), upregulation of immune checkpoints ( PD-1, PD-L1, TIGIT, LAG-3, VISTA ), and higher GATA3 and IFN-γ expression in obese pts (both p < 0.05). Multiplex CODEX analysis (n = 38; obese = 17, non-obese = 21) revealed an increased co-expression between GATA3 , a regulator of T-cell dysfunction, and granzyme B , a cytotoxic T-cell marker (Pearson ρ = 0.24, p < 0.05), indicating increased abundance of GATA3 ⁺granzyme B⁺ cells in obese pts. Conclusions: In CCA, obesity characterized by predominant subcutaneous adiposity is linked to improved outcomes with ICIs and to a biologically distinct TME enriched in dysfunctional cytotoxic T-cells that may be reinvigorated by checkpoint inhibition. BMI may represent a pragmatic biomarker warranting prospective validation.